A rare PRSS1 p.S127C mutation is associated with chronic pancreatitis and causes misfolding-induced ER-stress.
Cationic trypsinogen
Chronic pancreatitis
ER-Stress
Genetic risk
Journal
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
ISSN: 1424-3911
Titre abrégé: Pancreatology
Pays: Switzerland
ID NLM: 100966936
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
received:
12
10
2022
revised:
25
10
2022
accepted:
26
10
2022
pubmed:
12
11
2022
medline:
7
12
2022
entrez:
11
11
2022
Statut:
ppublish
Résumé
/Objectives: Sequence variants in several genes have been identified as being associated with an increased inherited risk to develop chronic pancreatitis (CP). In a genetic survey of a CP patient we identified in the PRSS1gene a new c.380C > G sequence variation, giving rise to a non-synonymous p.S127C mutation. Functional studies were performed to analyze the associated pathophysiology of the variant. Following generation of an expression vector for the new PRSS1 variant we compared its expression, secretion and catalytic activity with already known PRSS1 risk variants in HEK 293T cells. The intracellular protein accumulation and induction of endoplasmic reticulum (ER)-stress was analyzed. Prediction tool analysis indicated a probably deleterious effect of the p.S127C variant on protein function which was confirmed by detection of a secretion defect in HEK293T cells leading to intracellular protein accumulation. While protein misfolding was associated with reduced trypsin activity, the increased expression of BIP and presence of spliced XBP1 indicated that the p.S127C variant induces ER stress and activates the UPR signaling pathway. The disease mechanism of the PRSS1 p.S127C variant involves defective protein secretion and the induction of ER-stress due to accumulation of presumably misfolded trypsinogen within the ER. The new variant should be considered disease-causing with an incomplete penetrance. Our results confirm that in addition to dysregulated trypsin-activity or reduced fluid secretion, ER-stress induction is an important trigger for acinar cell damage and the development of recurrent or chronic pancreatic inflammation.
Sections du résumé
BACKGROUND
BACKGROUND
/Objectives: Sequence variants in several genes have been identified as being associated with an increased inherited risk to develop chronic pancreatitis (CP). In a genetic survey of a CP patient we identified in the PRSS1gene a new c.380C > G sequence variation, giving rise to a non-synonymous p.S127C mutation. Functional studies were performed to analyze the associated pathophysiology of the variant.
METHODS
METHODS
Following generation of an expression vector for the new PRSS1 variant we compared its expression, secretion and catalytic activity with already known PRSS1 risk variants in HEK 293T cells. The intracellular protein accumulation and induction of endoplasmic reticulum (ER)-stress was analyzed.
RESULTS
RESULTS
Prediction tool analysis indicated a probably deleterious effect of the p.S127C variant on protein function which was confirmed by detection of a secretion defect in HEK293T cells leading to intracellular protein accumulation. While protein misfolding was associated with reduced trypsin activity, the increased expression of BIP and presence of spliced XBP1 indicated that the p.S127C variant induces ER stress and activates the UPR signaling pathway.
CONCLUSIONS
CONCLUSIONS
The disease mechanism of the PRSS1 p.S127C variant involves defective protein secretion and the induction of ER-stress due to accumulation of presumably misfolded trypsinogen within the ER. The new variant should be considered disease-causing with an incomplete penetrance. Our results confirm that in addition to dysregulated trypsin-activity or reduced fluid secretion, ER-stress induction is an important trigger for acinar cell damage and the development of recurrent or chronic pancreatic inflammation.
Identifiants
pubmed: 36369231
pii: S1424-3903(22)00755-4
doi: 10.1016/j.pan.2022.10.005
pii:
doi:
Substances chimiques
Trypsin
EC 3.4.21.4
Trypsinogen
9002-08-8
PRSS1 protein, human
EC 3.4.21.4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1112-1119Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors report no conflicts of interest.